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Utilizing chemotherapies to alter the balance between life and death in the ER stress response of cancer

UTILIZING CHEMOTHERAPIES TO ALTER THE BALANCE BETWEEN LIFE AND
DEATH IN THE ER STRESS RESPONSE OF CANCER
by
Encouse B. Golden
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PATHOBIOLOGY)
August 2009
Copyright 2009 Encouse B. Golden

When the protein load is lower than the endoplasmic reticulum (ER) folding capacity, the ER master regulator, GRP78, suppresses ER unfolded protein response (UPR) signaling pathways. However, when the protein load acutely exceeds the protein folding capacity of the ER, GRP78 relinquishes its suppression of UPR pathways and assists in proper protein folding, thereby preventing protein aggregation. As a consequence, UPR activation results in the general attenuation of protein translation, ER-associated protein degradation (ERAD) of misfolded proteins, up-regulation of ER chaperones, and a return of the ER towards its baseline protein load. Remarkably, when the protein load greatly exceeds the folding capacity of the ER for a prolonged period of time, the cell initiates programmed cell death.; Since tumor cells thrive in harsh microenvironments and are metabolically hyperactive, they experience constant and moderate levels of ER stress. Consequently, tumor cells have developed adaptive cytoprotective mechanisms to deal with chronically elevated levels of ER stress. Overexpression of the ER chaperone GRP78, ubiquitin proteasome system (UPS), and autophagy are several survival mechanisms that afford tumor cells the ability to proliferate unrestrained, while exposed to suboptimal conditions, including hypoxia and exposure to chemotherapy. Thus, blocking any of the ER stress survival mechanisms may effectively trigger the apoptotic arm of the ER stress response.; This dissertation presents six novel strategies that utilize chemotherapies to alter the balance of life and death in the ER stress response of cancer cells. The first strategy includes the development and use of novel ER calcium depleting agents. The second strategy includes depletion of ER calcium in combination with UPS inhibition to synergistically kill tumor cells. The third strategy includes abstinence from green tea products to maximize UPS-inhibiting chemotherapies harboring boronic acid moeities. The fourth strategy includes the addition of green tea products to block GRP78 function and chemosensitize tumor cells to conventional chemotherapy. The fifth strategy includes the addition of an autophagy inhibitor to induce ER stress and chemosensitize tumor cells to conventional chemotherapy. Finally, the sixth strategy includes the development and use of a novel class of autophagy inhbitors to induce ER stress-associated apoptosis in tumor cells. Taken together, this dissertation demonstrates novel clinically applicable therapeutic strategies (involved in the disruption of tumor cell ER homeostasis) that hold promise in increasing tumor cell death and in decreasing cancer-associated rates of mortality.

UTILIZING CHEMOTHERAPIES TO ALTER THE BALANCE BETWEEN LIFE AND
DEATH IN THE ER STRESS RESPONSE OF CANCER
by
Encouse B. Golden
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PATHOBIOLOGY)
August 2009
Copyright 2009 Encouse B. Golden